Leptin
Also known as: OB protein, metreleptin, Myalept, adipokine, satiety hormone
Endogenous adipokine hormone — 167-amino-acid cytokine-like protein secreted by adipocytes; leptin receptor (LEPR/ObRb) agonist; anorexigenic agent; metabolic r
What it is
Leptin is a hormone made by fat cells that tells your brain you're full and your body has enough energy stored. It's used clinically — as metreleptin (Myalept) — by people with rare fat-wasting conditions called lipodystrophy, where the body can't make enough leptin, causing uncontrolled hunger, severe diabetes, and dangerously high triglycerides.
The scientific side
leptin is a 167-amino-acid adipokine secreted by adipocytes in direct proportion to fat mass, functioning as the primary hormonal signal of long-term energy reserves from the periphery to the central nervous system. Its canonical receptor, the long-form leptin receptor (ObRb/LEPR), is densely expressed in hypothalamic nuclei — particularly the arcuate, ventromedial, dorsomedial, and lateral hypothalamic areas — where leptin activates JAK2-STAT3 signaling to suppress orexigenic neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons and stimulate anorexigenic pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) neurons, producing a net reduction in food intake and increase in energy expenditure. Beyond hypothalamic regulation of energy balance, leptin exerts widespread metabolic effects at peripheral tissues: it stimulates hepatic VLDL-triglyceride export and reduces de novo lipogenesis, thereby limiting ectopic lipid accumulation and hepatic steatosis in lipodystrophic patients, as documented in controlled human studies showing decreased de novo lipogenesis markers following metreleptin treatment. In insulin-resistant states caused by leptin deficiency, exogenous leptin replacement substantially improves glycemic control and reduces insulin requirements independently of caloric intake, indicating direct insulin-sensitizing actions at the liver and skeletal muscle that operate in parallel with, but not exclusively through, its anorexigenic effects. Leptin also exerts vascular-protective effects by suppressing endothelial-to-mesenchymal transition (EndMT), which otherwise impairs endothelial function and promotes atherosclerosis in leptin-deficient states. Centrally, functional MRI studies in leptin-deficient lipodystrophy patients demonstrate that metreleptin treatment markedly increases hypothalamic resting-state connectivity and modulates reward-circuit activity, including responses in the ventral striatum, amygdala, and prefrontal cortex — effects that persist even for non-food reward stimuli, suggesting leptin shapes broader motivational states beyond appetite. In obesity, chronically elevated leptin fails to suppress appetite, a state termed leptin resistance, mechanistically linked to mTOR pathway hyperactivation reducing LEPR signaling, ER stress impairing hypothalamic leptin sensitivity, and complement-mediated neuroinflammation. In leptin-deficient conditions such as congenital leptin deficiency and lipodystrophy, metreleptin replacement additionally normalizes IGF-1 concentrations, restores linear growth in children, and appears to exert antidepressant effects. Novel LEPR agonist antibodies (e.g., REGN4461/mibavademab) aim to activate leptin signaling independent of endogenous leptin.
Class: Endogenous adipokine hormone — 167-amino-acid cytokine-like protein secreted by adipocytes; leptin receptor (LEPR/ObRb) agonist; anorexigenic agent; metabolic regulator; recombinant therapeutic form: metreleptin
Administration & storage
- Administration
- Subcutaneous injection (abdomenthighor upper arm) — standard clinical route for all reported studiesSelf-injection with insulin-type syringes or pen devices after trainingRotation of injection sites to prevent lipohypertrophy
- Storage
- Unopened Myalept vials should be refrigerated at 2–8°C (36–46°F) and protected from light. Do not freeze. Once reconstituted, the solution must be refrigerated and used within 3 days. Discard any unused reconstituted product after 3 days. Vials are for single patient use only.
- Cautions
- Anti-metreleptin antibodies with neutralizing activity have been reported and can cause loss of efficacy and worsening of metabolic disease; mandatory antibody monitoring is part of the REMS program,T-cell lymphoma has been reported in patients with acquired generalized lipodystrophy treated with metreleptin; causality is uncertain but a pharmacovigilance assessment found no definitive signal beyond underlying disease risk,Hypoglycemia risk when co-administered with insulin or insulin secretagogues — insulin dose reduction is usually required at treatment initiation,Autoimmune disease progression has been reported in patients with acquired lipodystrophy who have underlying autoimmune conditions,Myalept is available only through the REMS program due to the above risks; prescribers and pharmacies must be enrolled,Not approved for use in HIV-associated lipodystrophy or in obesity without lipodystrophy
Legal & regulatory status
Metreleptin (Myalept) was approved by the US FDA in February 2014 for treatment of the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy. It is available as a…
Leptin and leptin receptor agonists are prohibited under the World Anti-Doping Agency (WADA) Prohibited List under Section S2 — Peptide Hormones, Growth Factors, Related Substances and Mimetics — and are banned both…
Metreleptin (Myalept) has not received a Notice of Compliance (NOC) from Health Canada as of the reviewed literature and is not an approved therapeutic drug in Canada. Patients in Canada with lipodystrophy requiring…
What it's studied for
- Generalized lipodystrophy — metabolic complication treatment (FDA-approved indication) Human RCT / Regulatory approval
- Hepatic steatosis and NASH in leptin-deficient patients — reversal of liver fat Human open-label trial
- Partial lipodystrophy — improvement in glycemia and dyslipidemia Human observational / open-label
- Congenital leptin deficiency in children — growth restoration and metabolic normalization Human cohort study
- Anorexia nervosa — modulation of psychological and behavioral starvation adaptations Mechanistic review / early clinical exploration
- Brain connectivity and reward processing — CNS effects of leptin replacement Human neuroimaging study
- Leptin resistance in common obesity — investigational reversal via mTOR inhibition and novel LEPR agonists Preclinical / Phase 1 human
Safety signals
- Anti-metreleptin neutralizing antibodies causing loss of efficacy and acute metabolic deterioration
- T-cell lymphoma in patients with acquired generalized lipodystrophy on metreleptin
- Hypoglycemia — excessive glucose lowering when metreleptin added to existing insulin or oral antidiabetic regimens
- Worsening autoimmune disease — progression of underlying autoimmune conditions reported in some AGL patients
- Injection site reactions — local pain, erythema, and lipoatrophy or lipohypertrophy at injection sites
- Elevated Growth Differentiation Factor 15 (GDF-15) in hypoleptinemia-associated lipodystrophy — potential biomarker of metabolic stress rather than drug effect
- Metreleptin failure or acute worsening when neutralizing antibodies appear — case illustrating need for alternative downstream pathway agonists
All studies (2)
Frequently asked
Is leptin or metreleptin used for weight loss in people without lipodystrophy?
Metreleptin (Myalept) is FDA-approved only for the metabolic complications of generalized lipodystrophy, a rare condition involving near-total absence of body fat and very low leptin levels. It is not approved for, and clinical trials have not established efficacy in, weight loss for common obesity. People with obesity typically have high leptin levels and leptin resistance — not leptin deficiency — so additional leptin does not produce the expected appetite-reducing effect. Off-label use in obesity is not supported by current evidence.
Why does leptin not work for weight loss in most obese people?
Most people with obesity have high circulating leptin levels but have developed leptin resistance, meaning the brain no longer responds normally to leptin's satiety signal. Research suggests this involves chronic mTOR pathway overactivation that blunts hypothalamic leptin receptor signaling, as well as ER stress and neuroinflammation in key brain areas. This is why simply giving more leptin to people with obesity does not reliably reduce appetite or body weight — the problem is impaired signal reception, not signal absence.
What are the risks of metreleptin treatment?
The most serious risks are: (1) development of anti-metreleptin antibodies with neutralizing activity, which can cause the treatment to stop working and trigger rapid metabolic deterioration; (2) a potential association with T-cell lymphoma, primarily reported in patients with acquired generalized lipodystrophy (causality remains uncertain); and (3) hypoglycemia when metreleptin is used alongside insulin or antidiabetic medications, requiring dose reduction. For these reasons, Myalept is available only through a restricted REMS program in the United States. Any use should be under specialist supervision.
How is metreleptin administered and how often is it given?
Metreleptin is given as a subcutaneous (under-the-skin) injection, typically once daily, at a weight-based dose starting around 0.06 mg/kg/day. The lyophilized powder must be reconstituted with bacteriostatic water before injection. Injection sites (abdomen, thigh, or upper arm) should be rotated to avoid local reactions. Some patients require twice-daily dosing. Dose is adjusted based on metabolic response, and insulin doses usually need to be reduced when starting metreleptin. Patients and caregivers are trained to self-inject.
Does leptin affect the brain beyond just hunger?
Yes. Functional MRI studies in leptin-deficient patients show that metreleptin treatment significantly increases brain connectivity in the hypothalamus, limbic system, and prefrontal cortex, and alters reward-circuit responses to non-food stimuli such as monetary rewards. Studies also found suggestive antidepressant effects in lipodystrophy patients. This is consistent with leptin receptors in multiple brain regions involved in mood, motivation, and reward processing. In conditions of leptin deficiency — including severe anorexia nervosa — hypoleptinemia is thought to contribute to depression, hyperactivity, and impaired satiety signaling beyond simple hunger.